Trial of Ixazomib for Kaposi Sarcoma

Sponsor

AIDS Malignancy Consortium (Other)

Overall Status

Suspended

CT.gov ID

NCT04305691

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

54.3

Anticipated Duration (Months)

20.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well ixazomib works in treating patients with Kaposi sarcoma. Ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Kaposi Sarcoma Skin	Drug: Ixazomib Citrate Other: Quality-of-Life Assessment Other: Questionnaire Administration	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

Determine the overall response rate of ixazomib in participants with Kaposi sarcoma.

SECONDARY OBJECTIVES:

Determine safety and tolerability of ixazomib. II. Assess changes in Kaposi-sarcoma associated herpesvirus (KSHV) viral load (VL) by ixazomib.
Correlate changes in KSHV VL with tumor response. IV. For human immunodeficiency virus (HIV)-positive participants, assess changes in CD4 counts and HIV viral load.

EXPLORATORY OBJECTIVE:

Assess changes in quality of life during ixazomib therapy.

OUTLINE:

Patients receive ixazomib orally (PO) on days 1, 8, and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with complete or partial response may continue treatment for an additional 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks, then periodically for up to 2 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

41 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2 Trial of Ixazomib for Kaposi Sarcoma

Actual Study Start Date :

Nov 20, 2020

Anticipated Primary Completion Date :

May 31, 2024

Anticipated Study Completion Date :

May 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ixazomib) Patients receive ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with complete or partial response may continue treatment for an additional 12 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Ixazomib Citrate Given PO Other Names: MLN-9708 MLN9708 Ninlaro Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies

Arm

Intervention/Treatment

Experimental: Treatment (ixazomib)

Patients receive ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with complete or partial response may continue treatment for an additional 12 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Ixazomib Citrate

Given PO

Other Names:

MLN-9708

MLN9708

Ninlaro

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Other: Questionnaire Administration

Ancillary studies

Outcome Measures

Primary Outcome Measures

Overall response rate [Up to 4 weeks post treatment]
The binomial proportion and its 90% one-sided confidence interval will be used to estimate the overall response rate. Response and progression will be evaluated in this study using the acquired Immunodeficiency syndrome (AIDS) Clinical Trials Groups (ACTG) response criteria for Kaposi sarcoma, as outlined in the AIDS Malignancy Consortium (AMC) Kaposi sarcoma Response Evaluation Manual of Procedures (MOP).

Secondary Outcome Measures

Incidence of adverse events [Up to 4 weeks post treatment]
Frequencies of toxicities will be presented by severity at the event and person level; 95% confidence intervals will be computed for the proportion of participants experiencing grade 3 and higher toxicities. The incidence of toxicity-related dose reductions and treatment discontinuations will be summarized.
Change in Kaposi-sarcoma associated herpes virus (KSHV) viral load (VL) [Baseline up to 4 weeks post treatment]
KSHV lytic gene expression over time will be summarized; changes will be graphed and explored using paired t-tests or Wilcoxon signed rank tests. KSHV levels will be correlated with tumor response by computing descriptive statistics and making exploratory comparisons according to response, as well as examining Spearman's rank correlations between tumor size KSHV levels.
Change in CD4 counts [Baseline up to 4 weeks post treatment]
Immune status over time will be summarized; changes in immune status will be graphed and explored using paired t-tests or Wilcoxon signed rank tests.
Change in human immunodeficiency virus (HIV) VL [Baseline up to 4 weeks post treatment]
HIV viral load over time will be summarized; changes in HIV VL will be graphed and explored using paired t-tests or Wilcoxon signed rank tests. HIV levels will be correlated with tumor response by computing descriptive statistics and making exploratory comparisons according to response, as well as examining Spearman's rank correlations between tumor size and HIV levels.
Complete response rate [Up to 4 weeks post treatment]
Complete response will be defined as the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks.

Other Outcome Measures

Change in quality of life [Baseline up to 4 weeks post treatment]
General estimating equations will be used to evaluate changes in the functional assessment of HIV Infection (FAHI) + Kaposi sarcoma (KS) (FAHI+KS) questionnaire measures over time, accounting for clustering of responses within participants. There are three supplemental statements regarding participant perception of KS-specific symptoms: pain, swelling, and physical appearance. Agreement with each of these statements is graded using a Likert scale from 0 to 4. Responses to these statements may be dichotomized to reflect positive or negative impact of these symptoms.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Ability to understand and the willingness to sign a written informed consent document
Participants must have histologically or cytologically confirmed cutaneous Kaposi sarcoma. Participants must have measurable disease with a minimum of five bi-dimensionally measurable KS cutaneous marker lesions. If fewer than five bi-dimensionally measurable marker lesions are available, the total surface area of the marker lesion(s) must be >= 700 mm^2
Participants must have documentation of HIV status. If HIV negative, documentation of a negative HIV rapid test within 21 days before enrollment. If HIV positive, documentation of HIV-1 infection by means of any one of the following:
Documentation of HIV diagnosis in the medical record by a licensed health care provider
Documentation of receipt of antiretroviral therapy (ART) (at least two different medications that do not constitute a prescription for pre exposure prophylaxis [PrEP]) by a licensed health care provider. Documentation may be a record of an ART prescription in the participant's medical record, a written prescription in the name of the participant for ART, or pill bottles for ART with a label showing the participant's name
HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL
Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay
Note: The term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally (e.g., United States [U.S.] Food and Drug Administration [FDA]). WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an extracellular interactome assay (E/CIA )that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
Life expectancy of greater than 3 months
Absolute neutrophil count: >= 1,000/mm^3 (within 21 days before enrollment)
Hemoglobin: > 8 g/dL (within 21 days before enrollment)
Platelets: >= 75,000/mm^3 (within 21 days before enrollment). Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before study enrollment
Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (within 21 days before enrollment)
If the elevated bilirubin is felt to be secondary to indinavir or atazanavir therapy, then subjects will be allowed on protocol without any limit on the total bilirubin if the direct bilirubin is normal
Creatinine:
Serum creatinine levels within normal institutional limits; or, creatinine clearance >= 30 mL/min (as calculated per the Cockcroft-Gault Equation (within 21 days before enrollment)
Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification within 6 months before study enrollment. To be eligible for this trial, participants must be class 2B or better within 6 months before enrollment
Ixazomib can cause fetal harm. For this reason and because proteasome inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control and another method such as hormone contraception simultaneously; abstinence) before study entry, the duration of study participation, and 90 days after completion of ixazomib administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception or abstain from heterosexual contact before the study, for the duration of study participation, and for 90 days after completion of ixazomib administration
If HIV positive, participants must have been on antiretroviral therapy with optimum anti-viral response for at least 6 months with no evidence of KS shrinkage in the last 3 months. Changes of antiretroviral therapy within the prior 6 months for toxicity/convenience reasons are allowed (as long as participants are on a stable regimen for 4 weeks, but if any changes in anti-HIV therapy are due to inadequate HIV control and occurred within the 6 months prior to protocol consent, the patient is not eligible until 6 months after optimal control is reached and there is no KS regression in the last 3 months
If HIV positive, must have been on stable anti-retroviral therapy for at least 4 weeks on a protease inhibitor (PI)-containing regimen or nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen of at least three drugs. The NNRTIs efavirenz and etravirine are moderate CYP3A4 inducers and are allowed. There should be no intention to change the regimen for the duration of the study. Participants who have a high likelihood of better HIV management with a new antiretroviral regimen should defer enrollment until the changes are in place and the new cART regimen meets the 4-week criteria

Exclusion Criteria:

Participants who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ixazomib or other agents used in study
Chronic systemic treatment using strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort is not allowed. Patients who are on chronic use of strong CYP3A inducers must come off 14 days before receiving ixazomib treatment. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months; or psychiatric illness/social situations that would limit compliance with study requirements. This includes infections requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment but excludes ongoing antibiotic therapy for opportunistic infection (OI) prophylaxis
Participants with a second prior or concurrent malignancy that has a natural history or treatment regimen that has the potential to interfere with the safety or efficacy assessment of the investigational regimen
Pregnant women are excluded from this study because ixazomib is expected to cause fetal harm if used during pregnancy. It is not known if ixazomib is excreted into breast milk, but due to the potential for serious adverse events in a nursing infant, breastfeeding must be discontinued during therapy and for 90 days after the last ixazomib dose
Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before entering the study
Participants who have not recovered from other adverse events due to prior anti-cancer therapy (i.e., have residual toxicity > grade 1), excluding alopecia
Participants who are seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). All participants will be required to be screened for hepatitis B. Participants with resolved infection (i.e. participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen (anti-HBc) and/or antibodies to hepatitis B surface antigen (anti-HBs) must be screened using real-time polymerase chain reaction (PCR) measurement of HBV deoxyribonucleic acid (DNA) levels. Participants who are PCR positive will be excluded. EXCEPTION: Participants with serologic findings suggestive of hepatitis B virus (HBV) vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
Participants diagnosed with hepatitis C who are hepatitis C antibody positive, whether hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and have liver function tests that conform to the protocol inclusion criteria
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing
Participants with grade 1 peripheral neuropathy with pain on clinical examination during the screening period
Major surgery within 14 days before enrollment
Participants with symptomatic visceral Kaposi sarcoma
Participants who have had prior treatment that included a proteasome inhibitor